Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C-:13]#[N:14].[K+].Cl.C#N>CN(C=O)C.O>[Cl:12][C:4]1[C:3]([CH2:2][C:13]#[N:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: [C-]#N
Reactant: O=C(O)c1cccc(CBr)c1Cl
Agent: C#N
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(bromomethyl)-2-chlorobenzoic acid [Aromatic Intermediate 11, step a] (13.2 g) in DMF (150 mL) was treated with a solution of potassium cyanide (7.23 g) in water (50 mL) and the resulting solution was stirred at room temperature overnight. The mixture was diluted with water (200 mL) and carefully acidified with concentrated hydrochloric acid (25 mL), venting any liberated HCN through bleach solution via a stream of nitrogen. After being stirred for 2 hours, the aqueous phase was extracted with ethyl acetate (3×250 mL). The combined organic phases were washed with water (3×250 mL) and brine (250 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a white solid. Yield 10.3 g.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11][CH2:10]1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([S:26](Cl)(=[O:28])=[O:27])=[C:21]([CH3:30])[CH:20]=1>ClCCl>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH3:30])[C:22]([S:26]([NH:8][C:9]2([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11][CH2:10]2)(=[O:27])=[O:28])=[C:23]([CH3:25])[CH:24]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COC(=O)C1(N)CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(NS(=O)(=O)c2c(C)cc(OC)cc2C)CCC1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
Triethylamine (13.9 mmol, 2.0 equiv.) was added at 0° C. to a solution of methyl 1-aminocyclobutanecarboxylate (6.97 mmol, 1 equiv.) in dichloromethane p.a. (20 ml), and the mixture was stirred for 10 minutes. 4-Methoxy-2,6-dimethyl-phenylsulfonyl chloride (8.36 mmol, 1.2 equiv.), dissolved in DCM (5 ml), was slowly added dropwise at the same temperature, and the mixture was stirred for 4 hours at 25° C. The reaction mixture was diluted with dichloromethane (100 ml), washed with distilled water (2×50 ml) and saturated sodium chloride solution (2×50 ml) and dried over sodium sulfate. The solvent was concentrated and the crude product was purified by column chromatography (15% ethyl acetate in hexane) to yield the desired product in the form of a white solid. Yield: 66%
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14]1)[CH2:7]2.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:38]([O:37][C:35]([CH2:34][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:14]1)[CH2:7]2)=[O:36])[CH3:39]
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)nn1CC1CCc2c(O)cccc2C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)C2
Yield: 84.1 %

Procedure:
A suspension of 2-[(1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (425 mg), ethyl bromoacetate (184 mg) and potassium carbonate (152.9 mg) in acetonitrile (15 ml) was refluxed for 6 hours. After cooling, the precipitated solid was filtered off and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 2-[(1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxy-2-naphthyi)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.43 g) as pale yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:15]([O:17]CC)=[O:16])[C@H:9]([C:11]([F:14])([F:13])[F:12])[CH3:10])=[O:6])[CH:2]=[CH2:3].[OH-].[Na+]>C1COCC1.C(O)C.O>[CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:15]([OH:17])=[O:16])[C@H:9]([C:11]([F:13])([F:14])[F:12])[CH3:10])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@H](C(=O)OCC)[C@@H](C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCOC(=O)N[C@H](C(=O)O)[C@@H](C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.50 g (22.9 mmol) of ethyl (3R)—N-[(allyloxy)carbonyl]-4,4,4-trifluorovalinate (diastereomer mixture) were dissolved in a mixture of in each case 28 ml of THF, ethanol and water, and 13.77 g (344 mmol) of sodium hydroxide were added at 0° C. Ice-cooling was removed and the reaction mixture was stirred at RT overnight. The mixture was then added to water, acidified with semiconcentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. This gave 4.39 g of the target product which was not purified any further (75% of theory, diastereomer ratio about 2.5:1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[N+:6]([O-:9])([OH:8])=[O:7]>C(OC(=O)C)(=O)C>[N+:6]([O-:9])([OH:8])=[O:7].[N+:6]([O:5][CH2:4][CH2:3][CH2:2][NH2:1])([O-:8])=[O:7]
Reactant: NCCCO
Solvent: CC(=O)OC(C)=O
Solvent: O=[N+]([O-])O
Product: NCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A solution of 3-amino-1-propanol (6.17 g, 82.2 mmol) was added, drop-wise, to an ice-cooled solution of fuming nitric acid (90%, 12 mL) in acetic anhydride (50 mL). The reaction was stirred in an ice-bath for 10 minutes and then at room temperature for 10 minutes. The solvent was evaporated under vacuum at 40° C. The residue was stirred in diethylether (200 mL) until the product precipitated. The mixture was filtered and the white crystalline solid was dried in vacuo to give the title compound (12.1 g, 80% yield). 1H NMR (300 MHz, DMSO-d6) δ 4.57 (br. t, 2 H), 2.8-3.0 (m, 2H), 1.98-1.93 (m, 2H). 13C NMR (75 MHz, DMSO-d6) δ 70.9, 36.1, 24.5. MS m/z 121 (M—NO3)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2.CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:29]=4[CH:30]=[CH:31][NH:32]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)noc2c1
Reaction time: 68 h
Yield: 103.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 16 mmol), K2CO3 (2.2 g, 16 mmol), KI (200 mg), 4-(3-chloropropoxy)indole (3.0 g, 14 mmol) and CH3CN (100 ml) was stirred at reflux under N2 for 7 hours and then at ambient temperature for 68 hours. Reflux was resumed for an additional 6 hours whereupon a TLC revealed incomplete reaction. K2CO3 (0.5 g, 4 mmol) was added and the reaction was stirred at reflux for 17 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The organic extract was washed with H2O and saturated NaCl and after drying over MgSO4 the solvent was removed to afford 5.7 g of a beige solid. The product was purified by preparative HPLC (Water's Associates Prep LC/System 500 using 2 silica gel columns and 4% MeOH--CH2Cl2 as eluent) to yield 3.4 g (61%) of a beige solid. Two consecutive recrystallizations from EtOH provided 2.3 g (41%) of a white powder, m.p.=129°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:26])[C:16]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:17][N:18]=3)[S:13][C:6]=12.[Cl-].[NH4+].C(O)C>[Fe].O>[F:1][C:2]1[CH:30]=[C:29]([CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:26])[C:16]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:17][N:18]=3)[S:13][C:6]=12)[NH2:31]
Reactant: Cn1c(CN2CCOCC2)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cn1c(CN2CCOCC2)cnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 90 °C
Yield: 82.5 %

Procedure:
A mixture of nitro compound 296 (907 mg, 1.932 mmol), iron powder (917 mg, 16.42 mmol) and ammonium chloride (89 mg, 1.661 mmol) in a solvent system ethanol (24.0 mL) and water (12.0 mL) was heated to 90° C. for 1 hr. The reaction mixture was filtered while hot and concentrated. The residue was purified by Biotage (MeOH.DCM, 0-20%, SNAP 25 g cartridge) to give title compound 297 (700 mg, 1.593 mmol, 82% yield) as a white solid. MS: 440 (MH+).
Reaction SMILES: CC([O-])(C)C.[K+].Cl[CH2:8][C:9]([NH:11][CH2:12][C@H:13]([OH:16])[CH2:14][OH:15])=[O:10].CO.Cl>O>[OH:15][CH2:14][C@@H:13]1[CH2:12][NH:11][C:9](=[O:10])[CH2:8][O:16]1
Reactant: O=C(CCl)NC[C@H](O)CO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1CO[C@H](CO)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
To a solution of t-BuOK (13.7 g, 122 mmol) in t-AmOH (175 mL) was added a solution of 2-chloro-N—[(S)-2,3-dihydroxypropyl]acetamide (8.1 g, 48.3 mmol) in t-AmOH (325 mL) at room temperature over 2 h. The resulting suspension was stirred for 1 h at room temperature. Methanol (50 mL) and water (5 mL) were added and the resulting solution was stirred for 0.5 h at room temperature before adjusting the pH to 5 by the addition of conc. HCl. The suspension was filtered and the solid washed with methanol. The filtrate was evaporated in vacuo, the resulting solid was slurried in methanol (50 mL) and filtered off to afford (S)-6-(hydroxymethyl)morpholin-3-one (1.3 g) as a white solid. A second crop was obtained by adding EtOAc (200 mL) to the filtrate and filtering the resulting solution through a silica plug (1×10 cm). The solvent was evaporated in vacuo to afford (S)-6-(hydroxymethyl)morpholin-3-one (3.9 g, overall yield 5.2 g, 82%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([N+:19]([O-])=O)[CH:4]=1.[C:22]([OH:25])(=[O:24])[CH3:23]>[Fe]>[C:22]([O-:25])(=[O:24])[CH3:23].[CH2:11]([C:10]1[NH:19][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=2[N:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)O
Reactant: COc1ccc(NC(=O)Cc2ccccc2)c([N+](=O)[O-])c1
Agent: [Fe]
Product: CC(=O)[O-]
Product: COc1ccc2nc(Cc3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Iron (Fe) (124.7 mmole, 6.97 g) is added to a solution of N-(4-methoxy-2-nitrophenyl) phenylacetamide (18.5 mmole, 5.0 g) in acetic acid (130 ml). The mixture is refluxed for two hours and is stirred at room temperature for 48 hours. The solvent is evaporated. Recrystallisation from ethyl. acetate gives the title product as a light yellow solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.C([Li])CCC.[Cl:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(OCC)C.C(OCC)(=O)C>[Br:7][C:5]1[CH:6]=[C:2]([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)[S:3][CH:4]=1
Reactant: Clc1ncccn1
Reactant: Brc1csc(Br)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Clc1nccc(-c2cc(Br)cs2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a cooled (−78° C.) solution of 2,4-dibromothiophene (1 g, 4.13 mmol) in diethylether (30 ml) was added n-butyl lithium (2.5M in Hexanes, 4.55 mmol, 1.82 ml). The solution was maintained at this temperature for 1 hour before the addition of 2-chloropyrimidine (0.47 g, 4.13 mmol) in a single portion. The mixture was maintained at −78° C. for a further 1.5 hours before being allowed to warm up to room temperature. Ethyl acetate (20 ml) was added followed by DDQ (0.94 g, 4.13 mmol). The reaction was stirred for a further 30 minutes before being concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2) (7:3—Hexanes:EtOAc) to give the desired product (0.42 g, 37%) as a pale yellow solid which corresponded to the title compound. m/z (LC-MSW, ESP):275 [M+H]+, R/T=4.72 mins.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:23][C:24]1[C:25]([O:40][CH3:41])=[N:26][C:27]([O:38][CH3:39])=[C:28]([Cl:37])[C:29]=1[C:30](=O)[C:31]([O:33]CC)=O.CC(O)=O>COCCO.CCOC(C)=O>[Cl:37][C:28]1[C:27]([O:38][CH3:39])=[N:26][C:25]([O:40][CH3:41])=[C:24]([Cl:23])[C:29]=1[C:30]1[C:31](=[O:33])[N:21]([CH3:22])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CNc1nc(Nc2ccc(N3CCOCC3)cc2)ncc1N
Reactant: CCOC(=O)C(=O)c1c(Cl)c(OC)nc(OC)c1Cl
Solvent: COCCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1nc(OC)c(Cl)c(-c2nc3cnc(Nc4ccc(N5CCOCC5)cc4)nc3n(C)c2=O)c1Cl
Yield: 50.5 %

Procedure:
A mixture of 0.60 g (2 mmol) of 5-amino-4-(methylamino)-2-[[4-(morpholin-4-yl)phenyl]amino]pyrimidine, 1.23 g (4 mmol) of ethyl 2-(3,5-dichloro-2,6-dimethoxypyridin-4-yl)-2-oxoacetate, and 1 mL HOAc in 20 mL 2-methoxyethanol is heated under reflux for 16 hours. Workup in EtOAc, followed by chromatography on silica, eluting with hexane-EtOAc (3:2), gives 0.55 g (51%) of the title compound (Compound 18): mp (EtOH) 275–276° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([OH:15])[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH3:20])[C:11]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([O:15][C:36](=[O:38])[CH3:37])[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH3:20])[C:11]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=3[S:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C(=O)N(CCN(C)C(=O)OCc2ccccc2)c2ccc(C)cc2S[C@H]1c1ccc(C)cc1

Procedure:
A mixture of 0.73 g of (-)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 5 ml of acetic anhydride and 0.1 ml of pyridine is treated in the same manner as described in Example 1-(2), whereby 0.92 g of (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained as an oil. (3) A mixture of 0.92 g of (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 2 ml of 25% hydrogen bromide-acetic acid and 2 ml of acetic acid is stirred at room temperature for 2 hours. The mixture is evaporated under reduced pressure to remove solvent. Toluene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. Ether is added to the residue, and the resultant crystals are collected by filtration and washed with ether. A mixture of the crystals thus obtained, 2 ml of ethanol and 2 ml of an aqueous 5% sodium hydroxide solution is stirred at room temperature for 2 hours. The mixture is adjusted to pH 8 with acetic acid, and then extracted with chloroform. The extract is washed with water, dried and evaporated under reduced pressure to remove solvent. The residue is converted to its hydrochloride and recrystallized from isopropanol. 0.32 g of (-)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride hemihydrate is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=O)C)[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:22]=[CH:21][C:20]2C(=[CH:16][CH:17]=[CH:18][C:19]=2[N:23]2[CH2:28][CH2:27][N:26]([CH2:29]CC3C=C(C=CC=3)N)[CH2:25][CH2:24]2)N=1.[C:38]([BH3-])#[N:39].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:9])[CH2:29][N:26]2[CH2:27][CH2:28][N:23]([C:19]3[CH:18]=[CH:17][CH:16]=[C:38]4[C:20]=3[CH:21]=[CH:22][C:13]([CH3:12])=[N:39]4)[CH2:24][CH2:25]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: [BH3-]C#N
Reactant: CC(=O)Cc1cccc(Br)c1
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2c(N3CCN(CC(C)c4cccc(Br)c4)CC3)cccc2n1
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A solution of zinc(ll)chloride (0.5 M, THF, 0.5 eq., 234 uL) was added to a stirred solution of 1-(3-bromophenyl)-2-propanone (50 mg) and 2-methyl-5-(1-piperazinyl)quinoline (D3) (2.0 eq., 107 mg) in methanol (1 ml). The mixture was stirred 10 minutes then a solution of sodium cyanoborohydride (1M, THF, 1.0 eq., 234 uL) was added. The resulting white mixture was stirred at room temperature until hplc showed the complete disappearance of starting material. The mixture was concentrated under reduced pressure, diluted with aqueous sodium hydroxide solution (1M), and extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The crude was purified by chromatography using a SPE cartridge (SiO2) with DCM-methanol (98:2) as eluent to afford the title compound (50 mg, 50% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][OH:5].F[C:7]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10]>CN(C=O)C>[CH2:4]([O:5][C:7]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10])[CH3:3]
Reactant: CCO
Reactant: N#Cc1cccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1c(F)cccc1C#N
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
NaH 60% dispersion in mineral oil (575 mg, 14.4 mmol) was added to a rt solution of EtOH (1.0 mL, 17.1 mmol) in DMF (6.0 mL). After stirring for 40 min at rt, the solution was cooled to 0° C., 2,3-difluorobenzonitrile (1.59 mL, 14.4 mmol) was added dropwise and stirring was continued for 1 h at rt. The rxn mixture was quenched with water and extracted with DCM (2×). The combined org. layers were dried (MgSO4), filtered and concentrated in vacuo to yield 2-ethoxy-3-fluorobenzonitrile as an orange oil. LC-MS B: tR=0.74 min; [M+H]++=no ionization. 1H NMR (CDCl3) δH: 7.66 (m, 2H), 7.27 (m, 1H), 4.32 (q, 2H), 1.35 (t, 3H).
Reaction SMILES: [FH:1].[FH:2].[F:3][Si](F)(F)F.[OH-:8].[Al+3:9].[OH-].[OH-].[F-:12].[Al+3].[F-].[F-]>>[OH2:8].[OH2:8].[OH2:8].[F-:3].[Al+3:9].[F-:1].[F-:3].[Al:9]([F:12])([F:2])[F:1]
Reactant: F[Si](F)(F)F
Reactant: F
Reactant: [OH-]
Agent: [Al+3]
Agent: [F-]
Product: F[Al](F)F
Product: O
Temperature: 93 °C
Reaction time: 5 h

Procedure:
A fluosilicic acid solution and aluminum hydroxide were reacted with each other in a molar ratio shown in Table 1, and the produced silica was separated by filtration to prepare a super-saturated solution of aluminum fluoride having a concentration of aluminum fluoride and a concentration of fluosilicic acid shown in Table 1. Aluminum fluoride particles having an average particle diameter of 78 μm (specific surface area of 36.8 m2 /kg) were added as seed crystals to this super-saturated solution of aluminum fluoride, the resulting solution was maintained at a temperature of 93° C., stirred at a rate of 1.5 m/sec for 5 hours, and aluminum fluoride was deposited on the surfaces of the seed crystals to grow seed crystal particles. After crystallization, the crystal particles were collected by filtration and dried at 105° C. for 3 hours to obtain aluminum fluoride trihydrate particles (AlF3 ·3H2O).
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([N:17]=[C:18]=[S:19])[CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([N:17]2[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:18]2=[S:19])[CH:16]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)cc1N1C(=O)CN(C)C1=S
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), 5-chloro-2-methylphenyl-isothiocyanate (9.18 g), triethyl amine (12 g) and chloroform (200 mL) was heated at reflux for 5 hours. The mixture was cooled to ambient temperature, washed with 1N HCl (2×200 mL), then with water (200 mL) The organic phase was evaporated to dryness. The residue was crystallized from ethanol to give the title compound (9.2 g) as a tan solid, m.p. 132°-134° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N, 11.00. Found: C, 51.79; H, 4.12; N, 10.73. Mass spectrum (El, M.+) m/z 254/256.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C@H:15]3[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[O:18])=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)C=1>>[O:18]=[C:9]1[C@@H:10]2[C@@H:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:16](=[O:17])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([O:1][C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:3][CH:4]=1
Reactant: O=C1[C@H]2CCCC[C@H]2C(=O)N1c1ccc(O)cc1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(N2C(=O)[C@H]3CCCC[C@H]3C2=O)cc1)c1ccccc1
Yield: 77.4 %

Procedure:
The title compound (293 mg, 77% yield, white crystals) was prepared from cis-2-(4-hydroxy-phenyl)hexahydroisoindole-1,3-dione (245 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl—carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=379 (M+1); Rt=4.08 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.C[Mg+].[Br-].[CH3:19]COCC>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:19][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Reactant: CCOCC
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc2ncc(C)nc2cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound is prepared using an adaptation of the published method of Tamao, et al. Tetrahedron, 1982, 38, 3347-3354. To a THF solution under argon is added 2-Chloro-6,7-dimethoxyquinoxaline (5 g, 26 mmol) and NiCl2(dppp) (0.14 g, 0.26 mmol). The reaction mixture is cooled to 0° C., and a 3 M solution of MeMgBr in Et2O (13 mL, 39 mmol) is added portionwise. The reaction mixture is allowed to warn to room temperature, stirred for 1 hour, then refluxed for 1.5 hours. The mixture is cooled, quenched with 10% HCl, stirred 10 minutes, then made basic with 5% NaOH. CH2Cl2 and H2O are added to the reaction, and the mixture stirred overnight. Additional CH2Cl2H2O, and NaCl are then added and the mixture is filtered. The resulting solution is poured into a separatory funnel, and the aqueous layers are washed 3× with CH2Cl2. The organic layers are combined, washed with brine, dried (MgSO4), concentrated onto silica gel, and chromatographed (50%-80% EtOAc/hexanes) to provide a orange solid (49% yield).